JP2017524705A - Methods to improve myocardial performance in Fontan patients using udenafil compositions - Google Patents

Abstract

The present invention relates generally to the field of using udenafil or a pharmaceutically acceptable salt thereof in patients who have undergone fontan surgery. [Selection figure] None

Description

CROSS REFERENCE TO RELATED APPLICATIONS This invention relates to US Provisional Patent Application No. 62,036,506 filed on August 12, 2014 and US Provisional Patent Application No. 62/186, filed June 29, 2015. No. 132 is claimed and the provisional application disclosure is specifically incorporated by reference.

  The present invention relates generally to the field of using phosphodiesterase E5 (PDE5) inhibitors in patients undergoing fontan surgery. Specifically, the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

I. Background on Fontan Surgery The Fontan Surgery or Fontan / Kreutzel Surgery is a palliative surgical procedure for children born with functional single ventricular congenital heart disease. Fontan is designed to continuously supply blood flow to the pulmonary and systemic circulation without the need for a right heart pump chamber. The surgery allows systemic venous blood to flow directly into the pulmonary circulation through arteries, capillaries, and systemic venous systems based on single ventricular impitas. This arrangement has improved the life expectancy of patients with single ventricular and pulmonary outflow stenosis compared to previous arterial shunts.

  The operation creates an anastomoses of the upper and lower vena cava and separates the systemic and pulmonary circulation to eliminate both hypoxemia and ventricular volume load. However, there is no ventricular pump that pumps blood into the pulmonary artery after Fontan surgery. Instead, blood returns from the body veins to the lungs by passive flow. This results in a circulation characterized by high central venous pressure, abnormal pulmonary vascular resistance, and chronic low cardiac output. Over time, these unique features of Fontan physiology result in a predictable and sustained reduction in cardiovascular efficiency, characterized by a progressive decline in athletic performance beginning after puberty. This decline in exercise tolerance correlates with increased symptoms of cardiovascular dysfunction and may result in hospitalization, enhanced heart failure management, or the need for transplantation.

  Those with Fontan circulation do not have “normal” cardiac physiology or function. Two major complications that can affect many “downstream” are the following for blood pressure that rises (“hypertension”) and decreases (“hypotension”) depending on its location (vein or artery): It is an effect. First, with Fontan circulation, there is “systemic venous hypertension”, which means that the blood pressure in the body's veins (blood returning to the heart) is higher than that of individuals with normal (not Fontan circulation) heart function. Means that. There are many negative consequences (congestive heart failure, edema or swelling, liver dysfunction, possibly protein-losing enteropathy) that can be caused by venous hypertension, basically related to the distribution of fluids in the body . The second complication is “pulmonary arterial hypotension”, where the blood pressure in the arteries toward or within the lung (ie, lung) is low compared to individuals with normal heart function. Again, there are many negative consequences associated with pulmonary arterial hypotension such as cyanosis (purple lips) or lack of exercise tolerance. Secondary medical diseases and deaths that occur following Fontan surgery (short or long term) are believed to result from changes in body and pulmonary blood pressure.

  Due to the significant single ventricular preload from the arterial shunt and the long-term effects of inefficient oxygenation, it is rare to survive longer than the 10s or 20s. Although 40 years ago it was uniformly fatal, neonates with single ventricular congenital heart disease in 2010 are now not only likely to survive, but are expected to survive. However, as these children grow into adolescence and adulthood, it is clear that there are significant limitations to this method. Although lifesaving, Fontan / Kreutzel surgery results in severe physiological injury with very severe consequences. Over time, pervasive abnormalities in the multi-organ system affect. Realistically, it is unlikely that a patient will survive to her 20s or 30s without any complications that may be related to life or death. Thus, there is a clear need to find a treatment that can ameliorate the dysfunction of Fontan surgery. This is especially true when taking into account the growing popularity of Fontan surgery, notably, Fontan surgery is the most frequent operation for congenital heart disease after age 2 It has become. W.M. Gersony, Circulation, 117: 13-15 (2008).

  Several studies examining the results of Fontan surgery have shown a decrease in survival beyond 15 years after surgery. Regardless of the technique of vena cava pulmonary artery anastomosis, there is a high risk of mortality that progresses with continued natural decline. Another study that morphologically examined the single left ventricle after Fontan surgery showed a one-to-four chance that he or she would die before reaching her late twenties. J. Rychik, “Forty Years of the Fontan Operation: A Failed Strategy,” Pediatric Cardiac Surgery Annual, 96-100 (2010).

  In view of the longevity of Fontan patients, researchers have explored medical therapies that address the side effects of Fontan surgery. In particular, children and young adults with single ventricular physiology have abnormal exercise tolerance after Fontan surgery. Strategies targeted at improving cardiac output and reducing central venous pressure will improve their overall health and mitigate the effects of this detrimental physiology.

  In one study, the PDE5 inhibitor sildenafil was found to significantly improve ventilation efficiency during maximal and submaximal exercise. In addition, improvement of oxygen consumption at the anaerobic metabolic threshold was suggested in the two subgroups. These findings suggest that sildenafil may be an important drug that improves motor performance after Fontan surgery in children and young adults with single ventricular physiology. Goldberg et al, Circulation, 123: 1185-1193 (2011).

  More recent studies have confirmed that sildenafil increases ventricular systolic elastance and improves ventricular arterial coupling in patients alleviated using Fontan circulation. Short-term sildenafil is well tolerated in most patients with only minor side effects. Shabanian et al., Pediatr. Cardiol., 34 (1): 129-34 (2013). The structure of sildenafil is shown below.

  In addition, the short-term effect of the PDE5 inhibitor tadalafil on hemodynamic response to exercise and exercise tolerance in patients with Fontan circulation was evaluated in a preliminary study. See http://clinicaltrials.gov/ct2/show/record/NCT01291069. Similar to the published sildenafil results, short-term treatment with tadalafil once daily improved ventilation efficiency and oxygen saturation in young Fontan subjects, but exercise tolerance remained unchanged. Menon et al., Circulation, 128: A16024 (2013). The chemical structure of tadalafil is shown below.

  To obtain optimal effects, the PDE5 inhibitor sildenafil or tadalafil may need to be given to Fontan patients for a long time to delay or prevent the onset of Fontan circulatory failure. Fontan surgery produces a chronic condition, and it is unlikely that short-term treatment-related mortality will be addressed when a child undergoing Fontan surgery becomes an adolescent or adult. This is especially true when Fontan insufficiency begins, and patients have unavoidable declines in hemodynamics and function leading to death or heart transplantation. Early experience of transplantation in patients with Fontan circulation had high surgical mortality and morbidity. Early Fontan transplant experience has found that the hypothesis that PVR is sufficiently low relative to the right ventricle of the transplanted tissue after heart transplant is not correct if the patient survives with Fontan circulation.

Both sildenafil and tadalafil are known to have undesirable side effects, but patients with pulmonary arterial hypertension (PAH) who switched from sildenafil to tadalafil have significantly different oxygen saturation, oxygen saturation after a significantly different 6-minute walk test, And show significantly different walking distances, indicating that PDE5 inhibitors are not interchangeable when used to treat heart or cardiovascular conditions. Sabri et al., Pediatr Cardiol, 35 (4): 699-704 (2014).
II. Background on PDE5 inhibitors and udenafil

  PDE5 is a class of phosphodiesterases that regulate a variety of cellular functions by catalyzing the hydrolysis of secondary signaling molecules (cGMP) and cyclic adenosine-3 ′, 5′-monophosphate (cAMP). Click guanosine-3 ', 5'-monophosphate (cGMP) specific phosphodiesterase. Boolell et al., Int'l J. Impot. Res., 8:47 (1996). Since PDE5 is present in the arterial wall smooth muscle in the lung, PDE5 inhibitors are usually used for the treatment of pulmonary hypertension, a disease that causes excessive fluid load on the pulmonary blood vessels as a result of damage to the right ventricle of the heart. Have been studied.

  Udenafil is a drug used in urology to treat erectile dysfunction. Udenafil belongs to a class of drugs called PDE5 inhibitors, which also includes sildenafil, tadalafil, and vardenafil. Typical dosages are 100 and 200 mg. Udenafil is available in Korea, Russia and the Philippines. In the United States, use is not approved by the US Food and Drug Administration.

Fontan surgery is temporary relief and not curative. However, in many cases, normal or near normal growth, development, exercise tolerance, and good quality of life can be achieved.
In 20/30% of cases, patients will eventually need a heart transplant.

  Modifications in the Fontan surgical model were one of the early stages of improving outcomes. Use of fenestration, multi-stage Fontan surgery, and better perioperative management have led to a significant reduction in mortality today. Nonetheless, there is a slow spontaneous decline in patients with arrhythmias, ventricular dysfunction, and complications such as protein leaking enteropathy (PLE) and rare clinical syndromes of template bronchitis. The management of exacerbating Fontan includes detailed hemodynamic and image evaluation to treat any treatable lesion such as stenosis in the Fontan circuit, early control of arrhythmia and maintenance of sinus rhythm, PLE and template bronchitis Symptomatic treatment, manipulation of systemic vascular resistance and pulmonary vascular resistance, and fontan conversion from less favorable atrial / pulmonary artery connection to extracardiac upper and lower vena cava pulmonary artery anastomosis with arrhythmia surgery. It is the only successful eventual relief in Fontan patients whose heart transplantation is still worse. However, heart transplantation is not a perfect solution because Fontan's circulation, such as worsening liver or kidney function, has already destroyed the body, so patients with Fontan's circulation are still unwell even after heart transplantation Sometimes.

  There is a need in the art for improved therapies associated with the complications or side effects of Fontan surgery for the purpose of extending the life of Fontan patients and avoiding or delaying the need for heart transplantation. There is also a need in the art for improved therapies that delay the onset of heart failure and improve the quality of life of patients who have undergone Fontan surgery. The present invention satisfies this need.

  In one embodiment, the present invention is directed to a method of treating, preventing, and / or minimizing conditions, symptoms, and / or side effects associated with a patient who has previously undergone Fontan surgery. In particular, the methods of the present invention are directed to the use of udenafil or a pharmaceutically acceptable salt thereof in single ventricular adolescent patients who have undergone Fontan surgery for remission of associated acute and chronic symptoms. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In one embodiment, the present invention is directed to a method for improving cardiac output in a patient undergoing Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In another embodiment, the present invention is directed to a method of reducing pulmonary vascular resistance in a patient undergoing Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In yet another embodiment, the present invention is directed to a method for improving exercise tolerance in a patient undergoing Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In one embodiment, the present invention is directed to a method for improving myocardial performance in a patient undergoing Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In an exemplary embodiment, the methods of the invention comprise administering a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof to a patient once a day.

  In another embodiment, the method of the invention comprises administering to a patient a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof twice a day.

  In another embodiment, the patient is a pediatric patient about 2 to about 18 years of age. Treatment of adult patients is also encompassed by the methods of the present invention.

  In yet another embodiment, the present invention is directed to an improved method of treating a patient who has undergone Fontan surgery, the method comprising comparing udenafil or a pharmaceutically acceptable thereof as compared to a patient prescribed a non-udenafil drug. Show improved patient compliance with possible salt dosing schedules.

  In one embodiment, the present invention is directed to an improved method of treating patients undergoing Fontan surgery, and the method of the present invention has fewer adverse events compared to conventional methods of treating such patients. Or cause less severe adverse events. In another embodiment, the methods of the invention produce few, if any, serious adverse events, moderate adverse events, or mild adverse events.

  In another embodiment, the method of the invention results in an improvement in the patient's maximum effort VO2 compared to the maximum effort VO2 without using the method of the invention (eg, without administration of udenafil). . For example, the improvement is about 5, about 6, about 7, about 8, about 9, about 10 as compared to VO2 at maximum effort when not using the method of the invention (eg, without administration of udenafil). , About 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more.

  In another embodiment, the methods of the invention result in an improvement in VO2 at the patient's anaerobic metabolic threshold compared to VO2 when not using the method of the invention (eg, without administration of udenafil). For example, the improvement is about 5, about 6, about 7, about 8, about 9, about 10 as compared to VO2 at maximum effort when not using the method of the invention (eg, without administration of udenafil). , About 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more.

  In another embodiment, the method of the present invention is compared to blood pool MPI or other disclosed criteria for ventricular function when the method of the present invention is not used (eg, without administration of udenafil). It provides an improvement in blood pool MPI or other disclosure criteria for ventricular function. For example, the improvement may be about 5, about 6, about 7, compared to blood pool MPI or other disclosed measures of ventricular function when the method of the invention is not used (eg, without administration of udenafil). About 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24 , About 25, about 26, about 27, about 28, about 29, or about 30% or more.

  In another embodiment, the method of the present invention is compared to the logarithm of reactive hyperemia index or other disclosure criteria for vascular function when not using the method of the present invention (eg, without administration of udenafil). , Improving the logarithm of the patient's reactive hyperemia index or other disclosure criteria for vascular function. For example, the improvement may be about 5, about 6, compared to the logarithm of reactive hyperemia index or another disclosed measure of vascular function when not using the method of the invention (eg, without administration of udenafil). About 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23 , About 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more.

And finally, in yet another embodiment, the method of the present invention may result in a characteristic pharmacokinetic profile. The pharmacokinetic profile is a C _{max of} 300-700 ng / ml, or more specifically about 500 ng / ml; a T _{max of} 1-1.6 hours, or more specifically about 1.3 hours; 2550-4150 ng Hour / ml AUCτ, or more specifically about 3350 ng · hour / ml; and 5110-8290 ng · hour / ml AUC _0-24 , or more specifically about 6701 ng · hour / ml. it can.

  The foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further description of the claimed invention. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following brief description of the drawings and detailed description of the invention.

FIG. 1 shows the percentage of subjects who reported at least one, three, or five adverse events per treatment group.

FIG. 2 shows the change in peak VO2 (ml / kg / min) at maximum effort from baseline (Day 1) to the last visit (Day 5 after dosing) for each treatment group. A positive change indicates an improvement.

FIG. 3 shows peak VO2 at maximum effort at baseline (Day 1) and last visit (Day 5 after medication treatment) by treatment group, with positive changes indicating improvement.

FIG. 4 shows the change in VO2 (ml / kg / min) at the anaerobic metabolic threshold from baseline (Day 1) to the last visit (Day 5 after dosing) for each treatment group. Changes indicate improvement.

FIG. 5 shows the peak VO2 at baseline (day 1) and final visit (day 5 after dosing treatment) anaerobic metabolic threshold by treatment group, with a positive change indicating improvement.

FIG. 6 shows the change in natural log of reactive hyperemia index from baseline (Day 1) to the last visit (Day 5 after medication treatment) for each treatment group. A positive change indicates an improvement.

FIG. 7 shows the natural logarithm (RHI) of reactive hyperemia index at baseline (Day 1) and final visit (Day 5 after medication treatment) by treatment group. A positive change indicates an improvement.

FIG. 8 shows the change in blood pool MPI from baseline (Day 1) to the last visit (Day 5 after dosing) for each treatment group. A negative change indicates an improvement.

FIG. 9 shows blood pool MPI at baseline (Day 1) and final visit (Day 5 after dosing) by treatment group. Negative changes indicate improvement.

FIG. 10 shows the change in tissue Doppler MPI from baseline (Day 1) to the last visit (Day 5 after dosing) for each treatment group. Negative changes indicate improvement.

FIG. 11 shows the tissue Doppler MPI at baseline (Day 1) and final visit (Day 5 after dosing) by treatment group. Negative changes indicate improvement.

FIG. 12 shows the change in mean isovolumetric contraction from baseline (Day 1) to the final visit (Day 5 after dosing) for each treatment group. Negative changes indicate improvement.

FIG. 13 shows the mean isovolumetric contraction at baseline (Day 1) and final visit (Day 5 after dosing) by treatment group. Negative changes indicate improvement.

FIG. 14 shows the change in mean isovolumetric relaxation from baseline (Day 1) to the last visit (Day 5 after dosing) by treatment group. Negative changes indicate improvement.

FIG. 15 shows the mean isovolumetric relaxation at baseline (Day 1) and final visit (Day 5 after dosing) by treatment group. Negative changes indicate improvement.

FIG. 16 shows (A) 37.5 mg every 24 hours, (B) 37.5 mg every 12 hours, (C) 87.5 mg every 24 hours, (D) 87.5 mg every 12 hours, and (E) 125 mg 24 Figure 4 shows individual concentration time curves stratified by hourly dosing regime.

FIG. 17 shows a concentration time concentration profile of udenafil in a subject. The solid line represents the actual measurement data, and the broken line represents the prediction data for the second time of the 12-hour dosing method. Data are expressed as mean ± standard deviation.

FIG. 18 shows a comparison of Cmax between various dosing regimes. The boxplot shows the 10-90th percentile and range of observations, and the middle line represents the median of the dosing regime. Significant differences: 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p <0.001; 37.5 mg every 12 hours vs. 87 .5 mg every 12 hours, p <0.001; 37.5 mg every 12 hours vs. 125 mg every 24 hours, p <0.01; 87.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.05.

FIG. 19 shows a comparison of (A) AUCτ and (B) AUC0-24 between various dosing regimes. The boxplot shows the 10-90th percentile and range of observations, and the middle line represents the median of the dosing regime. Significant differences: A) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p <0.001; 37.5 mg every 12 hours Vs. 87.5 mg every 12 hours, p <0.01; 37.5 mg every 12 hours vs. 125 mg every 24 hours, p <0.01; B) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.01 0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p <0.01; 37.5 mg every 12 hours vs. 87.5 mg every 12 hours, p <0.001; 87.5 mg every 24 hours vs. 87 .5 mg every 12 hours, p <0.001; 87.5 mg every 12 hours vs. 125 mg every 24 hours, p <0.001.

FIG. 20 shows a comparison of A) CL / F and B) V / F between various dosing regimes. The boxplot shows the 10-90th percentile and range of observations, and the middle line represents the median of the dosing regime. Significant differences: A) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.05; B) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p <0.01.

FIG. 21 shows DV (measured concentration) versus subject ID.

FIG. 22 shows time (time) versus subject ID.

FIG. 23 shows DV (actual concentration) versus time after administration (TAD).

FIG. 24 shows DV (measured concentration) versus time (time).

FIG. 25 shows individual visual plots (SID 1-12) including variations between measured concentration (DV) versus expected concentration (PRED) and individual prediction (IPRED) error versus time (time).

FIG. 26 shows individual visual plots (SID 13-24) including variations between measured concentration (DV) versus expected concentration (PRED) and individual prediction (IPRED) error versus time (hours).

FIG. 27 shows an individual visual plot (SID 25-30) including variation between measured concentration (DV) versus expected concentration (PRED) and individual prediction (IPRED) error versus time (time).

FIG. 28 shows a summary of mean plasma concentrations per time point of udenafil pharmacokinetic study in Fontan patients. Data are shown as mean ± standard deviation.

FIG. 29 shows a non-compartmental analysis of udenafil in Fontan patients stratified by dosing regimen. Data are shown as mean ± standard deviation.

FIG. 30 shows a goodness-of-fit plot of measured data versus predicted data (DV vs. PRED).

FIG. 31 shows a goodness-of-fit plot of measured data versus individual predicted data (DV vs. IPRED).

FIG. 32 shows a goodness-of-fit plot of actual data versus predicted data (DV vs. PRED) for the final model.

FIG. 33 shows a goodness-of-fit plot of measured data versus individual predicted data (DV vs. IPRED) for the final model.

FIG. 34 shows the characteristic Fontan physiology.

I. Fontan Physiology Fontan physiology is a limited relief against a class of congenital heart defects that share the common feature of a functional single ventricle. They include disorders that produce dysplastic left or right ventricles. Usually, the systemic and pulmonary circulations are separated through a series of two or three operations to eliminate the mixing of oxygen-rich and oxygen-free blood. This is accomplished by connecting the superior and inferior vena cava directly to the pulmonary artery. This provides a physiology that operates as follows. (1) A single body ventricle pumps oxygen rich blood from the aorta to the body's systemic vascular bed. (2) Next, body venous blood returns by the vena cava and passively flows through the pulmonary vascular bed without the assistance of the subpulmonary artery. (3) Finally, oxygen rich blood returns to the common body atrium, and this circulation is repeated. This structure is illustrated in FIG.

  Fontan surgery creates an anastomoses of the upper and lower vena cava and separates the systemic and pulmonary circulation to eliminate both hypoxemia and ventricular load. However, there is no ventricular pump that pumps blood into the pulmonary artery after Fontan surgery. Instead, blood returns from the body veins to the lungs by passive flow. Thus, the main physiological consequence of this type of relaxation is that pulmonary blood flow is completely dependent on the pressure gradient from the systemic venous bed to the atria. Normal circulation flow through the pulmonary bed is augmented by the increased pressure generated by the right ventricle. In healthy adolescents, this increases the pressure present in the resting pulmonary artery by about 20-25 mm Hg and can double with exercise. With Fontan physiology, there is no pulmonary subventricular ventricle, so there is no increase in pressure as blood enters the pulmonary artery. At rest, the pressure gradient in the pulmonary vascular bed is extremely small. The ability to increase this pressure gradient with exercise is extremely limited by the body's ability to withstand increasing central venous pressure.

Fontan physiology is greatly affected by changes in pulmonary vascular resistance, since the unique outcome is to deliver pulmonary blood flow entirely dependent on passive reductions in venous pressure. Even an increase in pulmonary vascular resistance in normal physiology that is well within the normal range will have an adverse effect on Fontan physiology. Similarly, any decrease in resistance can increase pulmonary blood flow, even if the value is already normal. Thus, the use of udenafil provides a potential treatment specific to this class of alleviated congenital heart defects. Unlike other uses of PDE-5 inhibitors, this treatment would be less resistant in populations that do not have increased pulmonary vascular resistance or pulmonary vascular pressure. This is very rare with congenital heart disease and related pulmonary vascular disease that has been alleviated using structurally normal cardiovascular and pulmonary vascular disease or biventricular repair (and thus with pulmonary subventricular ventricles). This is a distinctly different use of this class of drugs compared to patients.
II. Clinical measurements related to Fontan patients

  Fontan surgery is the current treatment standard for children born with functional single ventricular congenital heart disease. Although Fontan surgery has greatly increased the survival of pediatric subjects, it is a temporary relief rather than curative, and the procedure also includes arrhythmias, ventricular dysfunction, protein-losing enteropathy (PLE) and templates It results in a series of side effects and complications that can lead to a late spontaneous decline in patients with complications such as rare clinical syndromes such as bronchitis and liver and kidney complications.

In certain embodiments, the disclosed invention relates to ameliorating or preventing a decrease in clinically relevant characteristic measurements of patient health following Fontan surgery. Such measurement results include, but are not limited to, exercise load tests, vascular function tests, and evaluation of ventricular function by echocardiography.
Exercise test

  Exercise testing can include assessment of VO2 values during maximum effort or at the anaerobic metabolic threshold. VO2max or maximum oxygen intake refers to the maximum amount of oxygen that an individual can use during strenuous exercise. This measurement is generally regarded as a reliable indicator of cardiovascular health and aerobic endurance. Theoretically, the more oxygen a person can use during a high level of exercise, the more energy he can produce. Because the muscles need oxygen for long-term (aerobic) exercise, the blood carries oxygen to the muscles, and the heart must pump enough blood to meet the demand for aerobic exercise. It is the most reliable standard for health status.

VO2 is often measured by putting the subject on a mask and measuring inspiratory and expiratory volumes and gas concentrations. This measurement is often used in both clinical settings and research and is considered the most accurate. Tests typically include gradual increases in intensity, exercise on a treadmill or riding on a bicycle until exhaustion, and are designed to give a reading of the subject's maximum effort and / or subject's anaerobic metabolic threshold. ing.

Patients previously undergoing Fontan surgery will generally experience a decrease in VO2 measurements over time. Treating a patient with the method according to the present invention, as a result of which the patient's VO2 measurement is maintained at the same level, indicating that there is no further decline in VO2 function, or that the VO2 measurement improves with treatment, It indicates that the treatment is clinically beneficial and can reduce or prevent a decrease in cardiovascular function.

  In one embodiment, the present invention is directed to a method of improving or maintaining VO2 measurements in a subject who has previously undergone Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, VO2 is measured at maximum effort, while in other embodiments, VO2 is measured at the subject's anaerobic metabolic threshold.

  In some embodiments, the methods and compositions of the present disclosure are administered to a Fontan patient, and exercise tolerance does not decrease over time, or a minimal decrease occurs. More specifically, the methods and compositions of the present disclosure are less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. May result in a decrease in exercise tolerance. The time between the first measurement and the second measurement used to calculate the decrease in exercise tolerance is, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, About 8, about 9, about 10, about 11, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 , About 12, about 13, about 14 or about 15 years, or any combination thereof, eg, 1 year 3 months; 4 years 7 months, etc.

In some embodiments, the methods and compositions of the present disclosure can be administered to a Fontan patient, resulting in improved exercise tolerance. More specifically, the methods and compositions of the present disclosure may improve 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more of the maximum effort VO2. Alternatively, the methods and compositions of the present disclosure may be greater than 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% of VO2 at the patient's anaerobic metabolic threshold. Can improve.
Vascular function test

  Vascular endothelial dysfunction is an important outcome for assessing vascular health in interventional studies. At present, vascular endothelial dysfunction is positively associated with traditional cardiovascular disease (CVD) risk factors and is well established to independently predict cardiovascular events over an interval of 1-6 years. ing.

  Pulse amplitude tonometry (PAT) is an FDA-approved method for assessing vascular function, an alternative measure of endothelium-dependent dilatation in response to reactive hyperemia and blood flow dependent vasodilatation (FMD). It is increasingly being used as. The PAT device records digital pulse wave amplitude (PWA) using fingertip plethysmography. PWA can be measured continuously during the three stages of resting baseline period, 5 min forearm occlusion, and reactive hyperemia after cuff release. Unlike FMD, PAT testing does not rely on highly skilled laboratory technicians, and post-test analysis is largely automated. More importantly, at least one long-term study has shown that the PAT criteria for endothelial function predict CVD events over a 6-year follow-up period. These great advantages can make PAT trials suitable for clinical practice if prognostic importance and reliability can be confirmed.

  Patients who have previously undergone Fontan surgery generally experience a decrease in vascular function over time. Treating the patient, resulting in an increase in the patient's vascular function or prevention of further decline in vascular function is clinically beneficial, improves the patient's quality of life, and improves cardiovascular function It is shown that it is possible to prevent a decrease in the image quality.

  In one embodiment, the present invention is directed to a method of improving or maintaining vascular function in a subject who has previously undergone Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, vascular function is measured using a PAT index.

  In some embodiments, the methods and compositions of the present disclosure are administered to a Fontan patient, and vascular function does not decrease over time, or minimal reduction occurs. Vascular function includes but is not limited to pulse amplitude tonometry measurements, natural log of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the maximum occlusion / control concentration curve, average to maximum occlusion / control, and other It can be measured using any conventional known technique including the known EndoPAT index. In some embodiments, vascular function is measured using a PAT index. More specifically, the methods and compositions of the present disclosure are less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. May result in decreased vascular function. The time between the first measurement and the second measurement used to calculate the decrease in vascular function is, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, 8, about 9, about 10, about 11, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, About 12, about 13, about 14, or about 15 years, or any combination thereof, eg, 1 year 3 months; 4 years 7 months, etc.

In some embodiments, the methods and compositions of the present disclosure can be administered to a Fontan patient, resulting in improved vascular function. Vascular function includes but is not limited to pulse amplitude tonometry measurements, natural log of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the maximum occlusion / control concentration curve, average to maximum occlusion / control, and other It can be measured using any conventional known technique including the known EndoPAT index. In some embodiments, vascular function is measured using a PAT index. More specifically, the methods and compositions of the present disclosure include, but are not limited to, pulse amplitude tonometry measurement, natural log of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the concentration curve relative to maximum occlusion / control, maximum About 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30 of one or more vascular function measurements, including average to occlusion / control and other known EndoPAT indicators , About 35, about 40, about 45, or about 50% or more improvement.
Echocardiographic evaluation of ventricular function

  Ventricular function or contractility is an important measurement that reveals cardiovascular health impairment before overt heart failure is found. Ventricular function can be assessed using echocardiography and can be quantified via myocardial performance index or MPI. MPI is an index that combines contractile function and dilated function. Specifically, MPI is defined as the sum of the isovolumetric contraction time and the isovolumetric relaxation time divided by the ejection time.

  Various versions of MPI are known in the art, and each version of MPI can be used to assess ventricular function. For example, the MPI index may include, but is not limited to, blood pool MPI, tissue Doppler MPI, mean isovolumetric contraction, and mean isovolumetric relaxation.

  Patients who have previously undergone Fontan surgery generally experience a decrease in ventricular function over time. Treating the patient so that the patient's ventricular function is maintained and shows a minimal decrease or increase over time is that the treatment is clinically beneficial, increases the patient's quality of life, It shows that it can prevent the decline of the function.

  In one embodiment, the present invention is directed to a method of maintaining, causing a minimal decrease in or increasing the ventricular function of a subject who has previously undergone Fontan surgery. . The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, ventricular function is measured using a myocardial performance index (MPI). In some embodiments, the MPI can be a blood pool MPI. On the other hand, in other embodiments, the MPI may be a tissue Doppler MPI.

  In some embodiments, the methods and compositions of the present disclosure are administered to a Fontan patient with minimal or no decrease in ventricular function over time. Ventricular function uses any conventional known technique including, but not limited to, myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumetric contraction and relaxation, and other known ventricular function indicators. Can be measured. More specifically, the methods and compositions of the present disclosure are less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. May result in decreased ventricular function. The time between the first measurement and the second measurement used to calculate the decrease in ventricular function is, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, 8, about 9, about 10, about 11, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, About 12, about 13, about 14, or about 15 years, or any combination thereof, eg, 1 year 3 months; 4 years 7 months, etc.

In some embodiments, the methods and compositions of the present disclosure are administered to a Fontan patient, resulting in improved ventricular function over time. Ventricular function uses any conventional known technique including, but not limited to, myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumetric contraction and relaxation, and other known ventricular function indicators. Can be measured. For example, the methods and compositions of the present disclosure include, but are not limited to, myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumetric contraction and relaxation, and any other known ventricular function index More than about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% or more of ventricular function as measured by known techniques Can lead to improvements.
III. Method according to the invention

  In one embodiment, the present invention is directed to a method of treating, preventing, and / or minimizing a condition, symptom, or side effect associated with a subject who has previously undergone Fontan surgery. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  In Fontan circulation, pulmonary blood flow is passive and is sent by the pressure difference between the systemic venous circulation and ventricular end-diastolic pressure. Agents that can more efficiently transport blood through the pulmonary vascular bed can improve cardiac output because it can improve pre-cardiac load.

  PDE5 inhibitors are a class of drugs that reduce pulmonary vascular resistance and improve ventricular function in patients with pulmonary hypertension and myocardial dysfunction.

  Several studies have evaluated single or long-term use of sildenafil in children and young adults undergoing Fontan surgery. However, sildenafil has a short half-life and is typically administered 3-4 times a day. Such a dosing schedule is not convenient and may reduce patient compliance. In addition, the administration of a short half-life drug results in large fluctuations in the therapeutic level of the drug, increasing the risk that the blood level of the PDE5 inhibitor will fall below the therapeutically effective level in part of the day . The inventors of the present invention hypothesize that administration of a PDE5 inhibitor with a longer half-life to a patient undergoing Fontan surgery will prevent or ameliorate the patient's decline in aerobic exercise capacity after Fontan surgery. .

  Patient compliance is critical for optimal therapeutic efficacy, especially for drugs that must be inoculated daily for long periods of time, such as several years or longer. This is especially true for Fontan patients. In particular, individuals who have undergone Fontan surgery most often die from heart failure, stroke (thrombosis), or some unexplained sudden death. It should be noted that the risk of death from heart failure is very low within 10 years of Fontan surgery, but increases over time from 10 years after Fontan surgery. http://bendantzer.wordpress.com/2013/03/13/fontan-circulation-success-or-failure/.

  Of course, over time from the day of Fontan surgery, the risk of death or the need for a heart transplant increases. This can be due to sudden death or heart failure, but can also be due to a gradual decline in heart function. As years pass after Fontan surgery, cardiac function worsens, which is reflected in a decline in the ability to perform aerobic exercise. For example, for patients who received Fontan in childhood, exercise tolerance may be significantly reduced (44%) compared to normal patients, and this exercise capacity tends to decrease linearly every year (2 .6% decrease). Patients with Fontan circulation have a significant decrease in exercise tolerance at age 30 (less than 55% below normal), and the number of health problems and hospitalization rates increase dramatically. Again, this is probably not surprising because one ventricle is doing two jobs. Thus, a method according to the present invention that can eliminate or significantly reduce the decline in cardiac function over time is highly desirable for Fontan patients. The key to the success of such a method is patient compliance with the preferred medication schedule.

  It is known that patient compliance with or lack of prescribed medication schedules is a critical factor in the success of any treatment. In particular, good health care outcomes depend on patient adherence to recommended treatment plans. Patient non-adherence is a prevalent threat to health and wellbeing and can also be a significant economic burden. In some conditions, over 40% of patients are at great risk by misunderstanding, forgetting, or ignoring healthcare advice. Moreover, if prevention or treatment planning is very complex and / or requires lifestyle changes and modification of existing habits, there can be as much as 70% non-adherence. Martin et al., Ther. Clin. Risk Manag., 1 (3): 189-199 (2005) ("But the big barrier to effective drug treatment is that the patient is his or her doctor or other health care provider. (Do not follow the recommendations of the (healthcare provider) "). Thus, multiple doses per day that need to be taken at least 4-6 hours apart, such as sildenafil, for example, preferred once or twice daily administration compared to 3-6 daily administrations. Treatments that can produce the desired result (eg, improved cardiac output, decreased pulmonary vascular resistance, improved exercise tolerance, improved myocardial performance, prevented or improved aerobic exercise capacity) are very desirable. Such more simplified administration regimes are likely to lead to a significant increase in patient compliance while at the same time improving treatment outcomes.

  In one embodiment, the present invention is directed to a method of improving cardiac output in a patient undergoing Fontan surgery, wherein the method provides a therapeutically effective amount of the PDE5 inhibitor udenafil or a pharmaceutically acceptable salt thereof. Administration. For example, the methods of the invention can be about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35 compared to subjects not receiving udenafil. %, About 40%, about 45%, or about 50% improvement in cardiac output.

  In another embodiment, the present invention is directed to a method of reducing pulmonary vascular resistance in a patient undergoing Fontan surgery, wherein the method administers to the patient a therapeutically effective amount of the PDE5 inhibitor udenafil or a pharmaceutically acceptable salt thereof. Including doing. For example, the methods of the invention can be about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35 compared to subjects not receiving udenafil. %, About 40%, about 45%, or about 50% reduction in pulmonary vascular resistance.

  In yet another embodiment, the present invention is directed to a method of improving exercise tolerance in a patient undergoing Fontan surgery, wherein the method provides a patient with a therapeutically effective amount of the PDE5 inhibitor udenafil or a pharmaceutically acceptable salt thereof. Administration. For example, the methods of the invention can be about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35 compared to subjects not receiving udenafil. %, About 40%, about 45%, or about 50% can result in an increase in exercise tolerance as measured by maximum VO2.

  In one embodiment, the present invention is directed to a method of improving myocardial performance in a patient undergoing Fontan surgery, the method comprising administering to the patient a therapeutically effective amount of a PDE5 inhibitor. For example, the methods of the invention can be about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35 compared to subjects not receiving udenafil. %, About 40%, about 45%, or about 50% improvement in myocardial performance.

  In one embodiment, the present invention is directed to a method of preventing or ameliorating a decline in aerobic exercise capacity in a patient undergoing Fontan surgery, the method comprising a therapeutically effective amount of the PDE5 inhibitor udenafil or a pharmaceutically acceptable salt thereof. Administration of a salt to a patient. For example, the methods of the invention can be about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35 compared to subjects not receiving udenafil. %, About 40%, about 45%, or about 50% can result in remission of reduced aerobic capacity as measured by maximum VO2.

  In yet another embodiment, the present invention is directed to an improved method of treating a patient who has undergone Fontan surgery, wherein the method is udenafil or a pharmaceutically acceptable product thereof compared to a patient prescribed a non-udenafil drug. Shows improved patient compliance with various salt dosing schedules.

Udenafil has a half-life of 7.3 to 12.1 hours and is believed to probably have a better safety profile compared to sildenafil or tadalafil. Udenafil has unique _{properties, T max} is 1.0 to 1.5 _hours, T _1/2 is 11 to 13 hours (a relatively fast onset of action and long duration of action). Therefore, both the use of udenafil on demand and the use once a day have been reported. The efficacy and tolerability of udenafil has been evaluated in several studies, and recent and ongoing studies indicate that udenafil is promising for both modes of administration. Currently, tadalafil is the only FDA-approved daily drug, but udenafil can be used as a once-daily dose for patients with erectile dysfunction who cannot tolerate tadalafil due to phosphodiesterase subtype selectivity. Gu Kang et al., Ther. Adv. Urol., 5 (2): 101-110 (2013). Once-daily administration of udenafil was evaluated for the treatment of erectile dysfunction (ED) and the results showed that udenafil markedly erectile function in ED patients when administered at a dose of 50 mg or 75 mg once a day for 12 weeks It showed that it improved. Zhao et al., Eur. J. of Urology, 60: 380-387 (2011). While these reports suggest that udenafil may be useful as a once-daily treatment for a variety of conditions, other reports indicate that PDE5 inhibitors have different efficacy in treating symptoms associated with Fontan surgery Indicates that Sabri et al., Pediatr. Cardiol., 35 (4): 699-704 (2014).

  Thus, the present invention directed to a method of treating and minimizing and / or preventing symptoms associated with Fontan surgery comprising administering udenafil or a pharmaceutically acceptable salt thereof is preferably It was surprising to show desirable results with once or twice daily administration. “Desirable outcomes” include improved cardiac output, decreased pulmonary vascular resistance, improved exercise tolerance, improved myocardial performance, prevented and improved aerobic exercise, and / or increased patient compliance However, it is not limited to these.

  In one embodiment of the invention, once-daily administration of a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof results in a therapeutic level of udenafil and is present in the patient's bloodstream for up to about 8 hours. In other embodiments of the invention, once daily administration of a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof is up to about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours, resulting in a therapeutic level present in the patient's bloodstream.

  In one embodiment of the invention, twice-daily administration of a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof results in a therapeutic level of udenafil for at least about 16 hours of the 24-hour administration period. In other embodiments, the twice-daily administration of a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof is at least about 9 hours, about 10 hours, about 11 hours, about 12 hours in a 24-hour administration period. Hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours Bring therapeutic levels of udenafil.

  In another embodiment, it was surprising that the methods of the present invention show improved results compared to prior art treatments using non-udenafil PDE5 inhibitors such as sildenafil or tadalafil. In yet another embodiment, it is surprising that the methods of the present invention show fewer and / or less severe side effects compared to prior art treatments using non-udenafil PDE5 inhibitors such as sildenafil or tadalafil. Was that.

  In one embodiment, administration of udenafil or a pharmaceutically acceptable salt thereof twice a day causes fewer side effects than administration of udenafil or a pharmaceutically acceptable salt thereof once a day. That is surprising. In another embodiment, it is surprising that twice-daily udenafil or a pharmaceutically acceptable salt thereof can achieve a therapeutically effective level of udenafil with a total daily dose of less than once-daily. That is.

In one embodiment, the patient undergoing Fontan surgery is a human patient. In one embodiment, the patient is an adult human patient older than 18 years. In another embodiment, the patient is a pediatric patient about 2 to about 18 years of age. In another embodiment, the patient is a pediatric patient from about 12 to about 18 years of age or from about 12 to about 16 years of age.
IV. Pediatric patient

  Because pediatric physiology is not just a reduced version of adults, the treatment of pediatric patients presents unique challenges. The physique is just one of many differences. Child body surface area, organ and system maturity and function, and cognitive and emotional development can result in differences in illness, diagnosis, treatment, and response to drugs. Due to children's unique anatomy and physiology, diseases seen in adults can even behave differently in children. In addition, because pediatric patients treat drugs differently than adults, the effects and doses of the drugs may vary more than those observed in adults. Children are different from adults in many other aspects of body size, so simply adjusting the dose of a drug for people with a small physique does not necessarily produce the same response, but causes an adverse drug reaction there is a possibility. Thus, the effects of drugs used to treat adult pathology do not predict successful treatment of pediatric patients with the same drugs.

  Thus, the present invention is also directed to the surprising discovery that pediatric Fontan patients can be successfully treated with the methods of the present invention. The method includes administering to a pediatric patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

  The structure of udenafil is shown below.

V. Dosage and dosage form

  In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 0.01 to about 150 mg / kg. In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 0.01 mg / kg up to about 30 mg / kg. In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 87.5 mg, Administered at a total daily dose of about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 275 mg. In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is about 25 mg, about 37.5 mg, about 50 mg, about 75 mg, about 87.5 mg, 125 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, It is administered at a total daily dose of about 675 mg, or about 700 mg. In another specific embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 37.5 mg, about 75 mg, about 87.5 mg, 125 mg, or about 175 mg.

  In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered once daily.

  In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered twice a day and the therapeutically effective blood level is at least about 18, about 19, about 20, about 21 in a 24-hour administration period. , About 22, about 23, or about 24 hours. In some embodiments, the total daily dose of udenafil or pharmaceutically acceptable salt administered twice daily is the daily dose of udenafil or pharmaceutically acceptable salt administered once daily. Less than total dose. In some embodiments, the total daily dose of udenafil or a pharmaceutically acceptable salt administered twice a day is 1 day per day for udenafil or a pharmaceutically acceptable salt thereof. Maintains therapeutically effective blood levels for the same amount of time as the higher dose when administered in multiple doses. In other embodiments, the total daily dose of udenafil or a pharmaceutically acceptable salt administered twice daily is 24 hours of udenafil or a pharmaceutically acceptable salt thereof once a day. Maintains therapeutically effective blood levels for a longer time compared to the same dose when administered.

  In some embodiments, udenafil or a pharmaceutically acceptable salt thereof administered twice a day is compared to udenafil or a pharmaceutically acceptable salt thereof administered once a day. Produces a greater reduction in conditions, symptoms, or side effects associated with subjects who have previously received

  In some embodiments, the pharmaceutically acceptable salt of udenafil is an acid addition salt. In one embodiment, the acid addition salt of udenafil is an inorganic acid addition salt such as a hydrochloric acid addition salt, a hydrobromic acid addition salt, a sulfuric acid addition salt, or a phosphoric acid addition salt. In another embodiment, the acid addition salt is citrate, tartrate, acetate, lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate), glycolate, Succinate, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate, aspartate, oxalate, benzenesulfonate, camphorsulfonate, cinnamate, adipate, Or organic acid addition salts such as cyclamate. In certain embodiments, the pharmaceutically acceptable salt of udenafil is oxalate, benzenesulfonate, camphorsulfonate, cinnamate, adipate, or cyclamate.

  In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition. In one embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated into a wide variety of oral or parenteral dosage forms for clinical application. Each dosage form can contain various disintegrants, surfactants, fillers, thickeners, binders, diluents such as wetting agents, or other pharmaceutically acceptable excipients.

  Udenafil composition is intranasal, buccal, sublingual, oral, rectal, ocular, parenteral (intravenous, intradermal, intramuscular, subcutaneous, intracisternal, intraperitoneal), pulmonary, intravaginal, topical ( Can be administered using any pharmacologically acceptable method, such as locally administered, topically administered, stamped topical administration, mucosal administration, aerosol, or via a buccal or nasal spray formulation .

  In addition, udenafil compositions can be in solid dosage forms, tablets, pills, troches, capsules, liquid dispersions, gels, aerosols, lung aerosols, nasal aerosols, ointments, creams, semisolid dosage forms, and suspensions. It can be formulated into any pharmacologically acceptable dosage form such as a liquid. Further, the composition may be a controlled release formulation, a sustained release formulation, an immediate release formulation, or any combination thereof. Further, the composition may be a transdermal delivery system.

  In another embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, where the solid dosage form is a powder, granule, capsule, tablet, or pill. be able to. In yet another embodiment, the solid dosage form can include one or more excipients such as calcium carbonate, starch, sucrose, lactose, microcrystalline cellulose, or gelatin. In addition, solid dosage forms can include lubricants such as talc or magnesium stearate in addition to excipients. In some embodiments, the oral dosage form can be an immediate release or modified release form. Modified release dosage forms include controlled release, sustained release, enteric release and the like. Excipients used in modified release dosage forms are well known to those skilled in the art.

  In a further embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated as a sublingual or buccal dosage form. Such dosage forms include sublingual tablets or solution compositions administered sublingually and buccal tablets placed between the cheek and gum.

  In yet a further embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated as a nasal dosage form. Such dosage forms of the invention include solutions, suspensions and gel compositions for nasal delivery.

  In one embodiment, the pharmaceutical composition can be formulated into a liquid dosage form for oral administration such as a suspension, emulsion, or syrup. In other embodiments, the liquid dosage form includes various excipients such as wetting agents, sweeteners, flavorings, or preservatives, in addition to widely used simple diluents such as water and liquid paraffin. be able to. In certain embodiments, a composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated to be suitable for administration to pediatric patients.

  In one embodiment, the pharmaceutical composition can be formulated into a parenteral dosage system such as a sterile aqueous solution, suspension, emulsion, non-aqueous solution, or suppository. In other embodiments, the non-aqueous solution or suspension can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate. As a suppository base, witepsol, macrogol, Tween 61, cacao butter, laurin oil, or glycerogelatin can be used.

The dosage of the pharmaceutical composition can vary depending on the patient's weight, age, sex, administration time and method, excretion rate, and disease severity.
VI. Adverse event

  Adverse events are important to consider, especially when treating sensitive populations such as pediatric patients with Fontan physiology. PDE-5 inhibitors can cause adverse events including eye and / or hearing problems. Accordingly, it is an aspect of the present invention to develop a method by which a PDE5 inhibitor such as udenafil or a pharmaceutically acceptable salt thereof can be safely administered to pediatric patients.

  In some embodiments, pediatric patients with Fontan physiology may be administered a PDE5 inhibitor to treat, minimize and / or prevent the deleterious effects of Fontan physiology. In some embodiments, administering a PDE5 inhibitor, specifically udenafil or a pharmaceutically acceptable salt thereof, results in minimal, if any, serious adverse events. In other embodiments, administering a PDE-5 inhibitor, specifically udenafil or a pharmaceutically acceptable salt thereof, results in minimal, if any, unexpected adverse events.

In some embodiments, pediatric patients with Fontan physiology receiving udenafil or a pharmaceutically acceptable salt thereof may experience only mild adverse events related to the drug, in other embodiments Patients may experience only moderate adverse events related to the drug. In some embodiments, pediatric patients with Fontan physiology receiving udenafil or a pharmaceutically acceptable salt thereof are less frequent compared to Fontan patients receiving another PDE5 inhibitor. May experience adverse events of low or low severity.
VII. Pharmacokinetic parameters

Pharmacokinetics refers to its absorption, distribution, metabolism, and excretion after the drug is administered to a subject. Drug kinetics affects drug efficacy and toxicity. The kinetic profile of a given drug can depend not only on the composition itself, but also on the dosage and mode of administration and how the drug is formulated and administered. Pharmacokinetic parameters that may be useful in determining clinical utility include plasma concentration, plasma concentration over time, maximum plasma concentration (C _max ), time to maximum concentration (T _max ), within dosing interval Area under concentration time curve (AUCτ), area under daily concentration time curve in steady state (AUC _0-24 ); CL / F, apparent clearance; V / F, apparent volume of distribution; ke, disappearance rate constant; Examples include, but are not limited to, T1 / 2 and terminal half-life.

  In some embodiments, the invention of the present disclosure is directed to a method of administering udenafil or a pharmaceutically acceptable salt thereof to a patient with Fontan physiology, the administration resulting in a unique pharmacokinetic profile. For example, in some embodiments, the methods of the present disclosure can be about 10 to about 700 ng / ml, about 50 to about 650 ng / ml, about 100 to about 600 ng / ml, about 150 to about 550 ng / ml, or about 200. Plasma concentrations of udenafil in the range of ~ 500 ng / ml can be produced. In other words, the mode of administration of the disclosed method is 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, Sustained plasma concentrations of udenafil can exceed 500, 525, 550, 575, 600, 625, 650, 675, or 700 ng / ml. In some embodiments, the plasma concentration is maintained above about 140 ng / ml.

In some embodiments, the disclosed method can have a C _max of about 25, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, About 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, about 675, or about Includes a characteristic pharmacokinetic profile that is 700 ng / ml. In some embodiments, C _max is about 506.

In some embodiments, the methods of the present disclosure have a T _max of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2. Characteristic pharmacokinetic profile that is 1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 hours (hours) including. In some embodiments, T _max is about 1.3 hours.

  In some embodiments, the methods of the present disclosure include a characteristic pharmacokinetic profile in which the area under the concentration curve (AUC) is specific to a therapeutically effective dose of udenafil in a Fontan patient. For example, AUCτ is 750 to 4500 ng · hour / ml, 800 to 4000 ng · hour / ml, or 850 to 3500 ng · hour / ml. More specifically, AUCτ is about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1400, about 1500, About 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200 , About 3300, about 3400, about 3500, about 3600, about 3700, about 3800, about 3900, about 4000, about 4100, about 4200, about 4300, about 4400, or about 4500 ng · hr / ml. In some embodiments, AUCτ is about 3350.

In some embodiments, AUC _0-24 is 750-8500 ng · hour / ml, 800-8000 ng · hour / ml, or 850-7500 ng · hour / ml. More specifically, AUC _0-24 is about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1400, About 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100 About 3200, about 3300, about 3400, about 3500, about 3600, about 3700, about 3800, about 3900, about 4000, about 4100, about 4200, about 4300, about 4400, about 4500, about 4600, about 4700, about 4800, about 4900, about 5000, about 5100, about 5200, about 5300, about 5400, about 550 0, about 5600, about 5700, about 5800, about 5900, about 6000, about 6100, about 6200, about 6300, about 6400, about 6500, about 6600, about 6700, about 6800, about 6900, about 7000, about 7100, About 7200, about 7300, about 7400, about 7500, about 7600, about 7700, about 7800, about 7900, about 8000, about 8100, about 8200, about 8300, about 8400, or about 8500 ng · hr / ml. In some _{embodiments, AUC 0-24} is about 6700.

In some embodiments, the pharmacodynamic results of administration to patients with Udenafil's Fontan physiology can be attributed to the characteristic pharmacokinetic profile of the drug administration or regimen.
VIII. Definition

  As used herein, the term “about” will be understood by those of ordinary skill in the art and will vary to some extent on the context in which it is used. Where the term is used and is not clear to one of ordinary skill in the art in view of the context in which it is used, “about” shall mean up to plus or minus 10% of the particular term.

  “Treatment” intends to target and combat the disease state, ie to ameliorate or prevent the disease state. Thus, the specific treatment will depend on the targeted condition and the current or future state of medical therapy and treatment methods. Treatment can be associated with associated toxicities.

  The term “administration” or “administering” the active agent provides the active agent of the present invention to a subject in need of treatment in a therapeutically useful form and in a form that can be introduced into a person in a therapeutically effective amount. It should be understood to mean that.

  The term “therapeutically effective amount” refers to an active agent of the invention in a suitable composition and suitable dosage form for treating or preventing the onset of symptoms, progression, or complications found in patients undergoing Fontan surgery. Of sufficient amount. The therapeutically effective amount will vary depending on the condition or severity of the patient's condition and the age, weight, etc., of the subject being treated. A therapeutically effective amount can vary depending on many factors, including, for example, the route of administration, the condition of the subject, as well as any other factors understood by those of skill in the art.

  The term “treatment” or “treating” generally refers to intervening to alter the natural history of the subject being treated and can be done for prevention or in the course of clinical pathology. Desirable effects include preventing the onset or recurrence of the disease, reducing symptoms, suppressing, reducing or inhibiting any direct or indirect pathological consequences of the disease, improving or alleviating the pathology And causing, but not limited to, remission or prognosis improvement.

  The terms “individual”, “host”, “subject”, and “patient” are used interchangeably herein.

  As used herein, “improving cardiac output” means an increase in the volume of blood pumped by the heart. Cardiac output is measured as a function of oxygen consumption.

  As used herein, the term “exercise tolerance” refers to the maximum amount of effort that a patient can sustain. Exercise tolerance can be measured by many different clinical techniques including interviews or direct measurements. The methods of the present invention include various methods of measuring exercise tolerance, including but not limited to riding a bicycle ergometer or walking on a treadmill. Thus, the term “improving exercise tolerance” means increasing the patient's ability to perform any level of effort or exercise.

  As used herein, the term “reducing pulmonary vascular resistance” refers to reducing or reducing the resistance provided to the bloodstream by the pulmonary vasculature.

  As used herein, “improving myocardial performance” includes, but is not limited to, a specific electrocardiogram reading, echocardiogram reading, cardiac output measurement, heart rate, Refers to an increase or decrease in specific cardiac function measurements including systolic or diastolic blood pressure, forced vital capacity, oxygen saturation, and respiratory rate.

  As used herein, “aerobic ability” refers to the ability of a patient to perform a specified aerobic exercise.

  As used herein, “children” refers to a population of subjects ranging from a newborn to about 18 years of age. Pediatric subjects are those who begin a series of treatments with the composition of the present disclosure or in accordance with the methods of the present disclosure before the age of about 18, even if the subject has been treated after about 18 years of age. Can be included. More specifically, within the population of “children” subjects, newborns are between 1 week and 1 month old, infants are between 1 and 2 years old, and infants are between 2 and 6 years old Can be defined as A child may refer to a subject age of 6-18 years.

  The following examples are given to illustrate the present invention. However, it should be understood that the invention should not be limited to the specific conditions or details described in these examples. All printed publications referred to herein are specifically incorporated by reference.

Example 1 Phase I / II Pharmacokinetic and Pharmacodynamic Study Phase I / II Dose Incremental Trial of Udenafil in Adolescents with Single Ventricular Physiology After Performing Fontan Mitigation

  The trial was conducted over 5 months with an additional 3 months follow-up period for adverse events (AEs). The 36 subjects enrolled in the trial consisted of the six cohorts listed in Table 1.

  The purpose of this study was to evaluate the safety of udenafil at multiple dose levels over 5 days, the pharmacokinetic profile of udenafil in adolescents with Fontan physiology, and the pharmacodynamics of exercise tolerance, ventricular function, and vascular function. It was to evaluate the short-term effect of udenafil against the evaluation criteria.

  Multiple doses of udenafil or a pharmaceutically acceptable salt thereof were administered to male and female Fontan patients aged 14-18 years.

The criteria for inclusion in this study are as follows.
• Men and women with Fontan menstruation aged 14-18 years • Willingness to return to the center to perform blood collection and testing as described in the study protocol • Patients will remain in the study period Must agree to refrain from alcohol, caffeinated beverages, and grapefruit juice • Informed consent by subject, and informed consent by parent / legal guardian as appropriate

Exclusion criteria for this study include:
• Non-cardiac medical, psychiatric and / or social disorders that may prevent the planned study from completing successfully or invalidate its results. • Height <132 cm (minimum of exercise testing) Height requirement)
• Known Fontan intracardiac tunnel occlusion, pulmonary artery branching stenosis, or pulmonary vein stenosis resulting in an average difference of> 4 mmHg between the proximal and distal regions of occlusion • Single lung physiology • Performed most recently Severe ventricular dysfunction or valve regurgitation determined by review of echocardiogram (atrial chamber valve or meniscal valve)
-Serious kidney damage (serum creatinine> 2.0), liver damage (serum AST and / or ALT> 3 times the upper limit of normal), absorption of orally administered drugs, metabolism, based on clinical examination at the screening visit Gastrointestinal or bile duct disorders that may impair excretion • Hospitalization for acute decompensated heart failure within 12 months prior to study screening • Diagnosis of active protein-losing enteropathy or template bronchitis • Active for heart transplantation Active evaluation or listed • History of use of PDE5 inhibitors within 3 months of study screening • In the opinion of the investigator, concomitant disease prevents participation • Current use of Alpha blockers or nitrates Treatment ・ Pregnant at registration ・ Latex allergy

  Table 2 shows the baseline characteristics for all 36 enrolled subjects (second column) and each of the six individual cohorts. The median age of enrolled subjects is 16 years (range 14-18 years). 58% were male, 78% were white, and 6% were Hispanic. There were no significant differences in baseline characteristics between cohorts (right column).

Example 2 Safety and Adverse Events The purpose of this example was to describe and evaluate the safety of the udenafil composition administered in the study described in Example 1.

  Tables 3-6 show the number of subjects who reported at least one AE. Data are shown by treatment group. The counts are shown for each AE category (Table 3) and for each basic word (Table 6). Tables 3-6 report all AEs by category (Table 3), severe AEs (Table 4), non-serious AEs (Table 5), and all AEs by basic word (Table 6). No serious AE was reported.

  Table 7 shows a narrative description of all adverse events categorized by cohort, subject, AE term, and basic term (limited to non-serious at the time of writing).

Attorney specification number: 107984-0107

Table 8 shows that the number of AEs per treatment group is ≧ n, where n = 1, 2,. . . , 6 indicates the number of subjects.

Tables 9-12 show AEs per basic word (similar to Table 6), but also related to number of subjects with AEs and number of AEs (Table 9), treatment groups and study drug (may be related or The number of AE events / subjects grouped by vs. no association (table 10), mild vs moderate / severe (table 11), and expected AE vs. unexpected AE (table 12). Report.

Table 13 is a subset of Table 7 limited to basic terms in which AEs occurred more than once in at least one cohort (≧ 2 AEs for one subject or ≧ 2 subjects for at least one AE) Pay attention to.

    FIG. 1 shows the percentage of subjects reporting at least one, three, or five (number taken from Table 6) adverse events per treatment group. The horizontal cohort is categorized from the lowest daily dose on the left (exercise only group; zero dose, not placebo) to the highest single dose on the right (125 mg). The percentage varies from 100% to 0% (exercise only group). As expected, the exercise only group is characterized by the lowest percentage. The plot does not suggest a clear association between the dose and the percentage of subjects reporting AE.

Example 3 Exercise Test The purpose of this example was to evaluate the effectiveness of the treatment protocol described in Example 1 using various exercise test parameters.

The primary outcome of this treatment group in this study was the maximum VO2 determined by exercise testing. Table 14 summarizes the results of the exercise outcome important outcome-peak VO2 (limited to subjects who achieved maximum effort) by treatment group. Of the 36 subjects enrolled in the trial, 33 reached maximum effort in the exercise test at each time point, and 31 subjects reached at both time points. The first two lines show baseline and follow-up measurement data, while the third line shows the difference between the two measurements (change score, outcome of this treatment group). Analysis of variance suggests no difference between change scores (p = 0.85).

  Figures 2 and 3 visually show the result of the change score (a positive change indicates an improvement). FIG. 2 shows the individual change scores for each subject with paired measurements (circles), with the two lines being the mean and median. The plot does not suggest that the change score increases with dose. FIG. 3 shows the maximum VO2 values before and after treatment for each subject and each cohort.

  As expected, the baseline and follow-up measurements are strongly correlated with a correlation coefficient> 0.8.

An additional outcome, VO2 at the anaerobic metabolic threshold, was also measured. A similar analysis was performed for this outcome. The results are shown in Table 15 and FIGS. The overall result is similar to that of maximum VO2.

  Of note, both exercise outcomes (peak VO2 and VO2 at the anaerobic metabolic threshold) are strongly correlated (correlation coefficient at each visit exceeds 0.7), similar to the trend lines in FIGS. Can explain sex.

Example 4 Vascular Function Test The primary outcome of vascular function was determined according to the Endothelial Pulse Amplitude Tonometry (PAT) index determined by the EndoPAT® device (Itamar Medical, Caesarea, Israel).

Table 16 summarizes the results for the natural logarithm (lnRHI) of the vital outcome-reactive hyperemia index of vascular function tests by treatment group. Of the 30 subjects enrolled in the study treatment group, 27 subjects had an acceptable quality paired measurement (QC score equal to 3 (best) or equal to 2). The structure of the table is the same as that of the motion variable.

  6 and 7 visually show the result of the change score (a positive change indicates an improvement). FIG. 6 shows the individual change scores for each subject with paired measurements (circles), with the two lines being the mean and median. The plot does not suggest that the change score increases with dose. FIG. 7 shows the lnRHI values before and after treatment for each subject and each cohort.

  Baseline and follow-up measurements are moderately correlated with an overall correlation coefficient of 0.4.

  Of note, both the mean baseline and follow-up measurements were proposed by the EndoPAT literature as a threshold between normal (defined as lnRHI> 0.51) and abnormal (lnRHI ≦ 0.51) values. It is close to the cutoff value of 0.51. Analysis of the data shows that some patients showed as much as 9.75% improvement on this criterion.

Table 17 reports change scores only for secondary EndoPAT outcomes (RHI, Framingham RHI, etc .; upper panel) and other EndoPAT indicators. In all cases, a positive change indicates a potential improvement.

Example 5 Echocardiographic Evaluation of Ventricular Function The primary outcome of ventricular function was evaluated using the echocardiographic method and measured according to the myocardial performance index (MPI). MPI is a measure of ventricular function that combines systolic and diastolic, independent of ventricular shape (Charles S. Kleinman et al, 2008-Health and Fitness). MPI can be obtained by using the sum of the isovolumetric systole and the relaxation phase as a function of ejection time.

Table 18 summarizes the results for the critical outcome-blood pool MPI of echocardiographic assessment of ventricular function. Of the 30 subjects enrolled in the trial treatment group, 27 subjects performed paired measurements. The structure of the table is the same as that of the motion variable. Analysis of the data shows that some patients showed as much as 21.5% improvement on this criterion.

  Figures 8 and 9 visually show the result of the change score (a negative change indicates an improvement). FIG. 8 shows the individual change score for each subject with paired measurements (circles), with the two lines being the mean and median. The plot does not suggest that the change score increases with dose. FIG. 9 shows blood pool MPI index values before and after treatment for each subject and each cohort.

  Baseline and follow-up measurements are strongly correlated with an overall correlation coefficient of 0.7 (last two lines). Of note, both the average baseline and follow-up measurements are in the elevated area (> 0.4).

Tables 19-21 and FIGS. 9-15 report similar results for the other three versions of MPI: tissue Doppler MPI, and mean isovolumetric contraction and relaxation.

  For these three additional MPI versions, negative changes again suggest a possible improvement, and the overall conclusion is the same as that of blood pool MPI.

  In addition, since a positive outcome was seen during the short-term study described in Examples 1-5, it is more beneficial to administer udenafil or a pharmaceutically acceptable salt thereof to a Fontan patient for a longer period of time. Can produce a strong pharmacodynamic outcome.

Example 6-Pharmacokinetic study NONMEM version 7.2, R, PDxPOP (R) 5, Xpose, and Phoenix WinNonlin were used for pharmacokinetic analysis.

  Pharmacokinetic analysis was performed on Fontan patients who received udenafil. FIG. 16 shows the results of data evaluation for individual subjects for each dosing cohort, and FIG. 17 shows the subject's udenafil concentration profile. Plasma concentrations were measured at various time points, non-compartmental analysis was performed in patients and stratified by dosing regimen.

Figures 18-20 show various comparisons between dosing cohorts. Based on non-compartmental analysis, C _max was significantly increased in the 87.5 mg 12-hour and 125 mg 24-hour cohorts compared to the 37.5 mg 12-hour or 24-hour cohort (FIG. 18).

The 87.5 mg 12-hour cohort showed an increase in C _max compared to the corresponding cohort every 24 hours (FIG. 18). AUCτ was significantly increased in the 87.5 mg 12-hour cohort and the 125 mg 24-hour cohort compared to the 37.5 mg 12-hour or 24-hour cohort (FIG. 19). AUC _0-24 was significantly increased in the 125 mg 24 hour cohort compared to the 37.5 mg 24 hour cohort. The 87.5 mg 12-hour cohort showed the highest increase in AUC _0-24 among all dosage regimes tested (FIG. 19). Except for a significant difference between 37.5 mg every 24 hours and 87.5 mg every 12 hours, there was no significant difference in CL / F or V / F between dosing regimes (FIG. 20). Among the five test mode of _{administration, k e, T 1/2} , also there was no statistically significant difference in _{T max} to.

  Population pharmacokinetic model development

Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model analysis method. This method estimates the representative values of the parameters and their variances. The subject was assumed to be in steady state (SS): time (t) after dose (D) was given at time tD after repeated administration of dose D given at interval τ (t ≧ t _D ). The PK sample / udenafil concentration was collected on the sixth day of testing.

  Since only day 6 drug administration is provided, the subject is expected to take the drug at regular intervals at home, which is why the steady state flag is tested and not available Will be explained. As described above, steady state is described because udenafil has been described in previous studies with multiple days of administration, steady state is reached in 5 days, and little further accumulation apparently occurs after 7 days of administration. Is assumed to be reached by day 6. If there is a missed dose during the test period prior to PK sampling, this may affect the ability to determine whether steady state can be assumed for the pharmacokinetic profile. If two or more additional drug administration dates and times were available prior to the visit at which the PK sample was taken, a better dosing profile would have been used for the analysis.

  Structural model

The 1- and 2-compartment models were examined (based on literature and available data). The equation for the drug input model described oral absorption. For the 1-compartment model, the following equation can be applied:

Considering that CL = k10 * V, the following equation can also be applied:

The 2-compartment model can be described by the following differential equation.

The amount of drug in the body after oral administration can be described by the following differential equation.

  The robustness of the final model was evaluated with PDxPOP® 5 by bootstrap resampling (n = 1000). The values obtained using bootstrap (bases based on all runs that were successfully minimized) were compared with parameter estimates from the final model. In order to evaluate the accuracy of model prediction, normalized prediction distribution error (NPDE) was performed.

  Some a priori information was used to guide the development of the model.

  The 1- and 2-compartment models containing the oral absorption input were evaluated using the initial estimates obtained from the above literature and examined in detail to determine the model possible structure. The objective function value, statistical significance level, goodness-of-fit plot, and standard error were used to evaluate the model during the model building process.

  The only covariate available for analysis was current body weight. Body weight was tested as a fixed effect on the typical values of clearance and distribution volume (eg, weight has a “fixed effect” on clearance). The median weight of the data set was 65.3 kg.

  The “representative value” of clearance was predicted for a 70 kg patient using the weight (WT) in the data set. Estimated THETA (1) and THETA (2) for subjects with known WT can be directly compared to CL and V values for subjects with “standard” weight, eg, WTs = 70 kg.

  Concerns sometimes expressed may be that scale parameter values estimated in children in terms of the 70 kg adult size standard may bias the estimate or affect the accuracy of the estimate. This concern is unfounded. This can be seen in examination of a relative growth scaled covariate model that can be reorganized and simply a constant determined by any weight chosen for normalization. The accuracy of the parameter estimate will not change by multiplying the parameter value by an ad hoc constant. The criterion for selecting covariate equations of model weight was statistical significance.

  21-29 show the results of pharmacokinetic data analysis.

  A number of residual error models were evaluated during the model building process. Proportional error model and exponential error model could not be performed and they were finished each time. Although the additive error model could be performed, the GOF plot did not fit well to the 1-compartment model and the 2-compartment model showed a better fit. Despite the high CV% of the residual variability, the mixed error model gave a good estimate of the other parameters at 95% CI and showed a good fit in the GOF plot visual inspection. A choice was made to use this model as the base model (FIGS. 30-31). It is possible to control high CV% if all doses on days 1-5 were included from each subject before the 6th day of sampling, and before and after sampling. It is possible. This does not need to be done because the model fit is good as described here, but this can further reduce the% CV.

  After comparing the measured and predicted data, a final model was created. The GOF plot of the final model is found in FIGS.

  We worked on bootstrap resampling and compared the parameter estimates of the final model with those determined after running 1000 bootstraps. In addition, visual predictive check (plot comparing 95% prediction interval with measured data) and normalized predictive distribution error (NPDE) method were applied to final model evaluation. In addition, visual postmortem performance was evaluated.

  Udenafil pharmacokinetics was well described by a two-compartment model including mixed addition and proportional error. Apparent clearance (CL / F) was scaled using adult weight, current weight normalized to 70 kg. Respiration rate constant is 0.28 hr-1 (95% CI 0.16-0.39), apparent clearance (CL / F / 70 kg) is 36 L / h (95% CI 28.5-43.1), Median distribution volume (V2 / F) is 74 L (95% CI 36.2 to 112), clearance between compartments (Q / F) is 21.1 L (95% CI 10.4 to 31.8), and peripheral distribution The volume (V3 / F) was estimated to be 181 L (95% CI 141-221). The final model was evaluated using bootstrap resampling, normalized prediction distribution error, and visual posterior performance evaluation methods. These methods showed that the final covariate model fits the data well.

  A two-compartment model that includes an absorption rate constant successfully describes the pharmacokinetics of udenafil in adolescents with single ventricular physiology after Fontan relaxation. There was a statistically significant effect on apparent clearance (CL / F) when subject body weight was normalized to the final model, adult body weight included in CL / F L / hr / 70 kg, 70 kg.

Example 7-Phase III Trial of Udenafil in Fontan Patients A phase III trial of Udenafil in Fontan patients was conducted in adolescent populations with a single ventricular congenital heart disease alleviated with Fontan surgery (87.5 mg, Safety twice a day). This study will also evaluate the pharmacodynamic profile of udenafil over a period ranging from at least 6 months up to 1 year. Pharmacodynamic outcomes will include exercise tolerance, echocardiographic measurements of ventricular function, endothelial function, and serum biomarkers, and functional health / quality of life measurements. Udenafil (87.5 mg twice daily) is expected to be safe and effective in improving exercise tolerance and other endpoints of cardiovascular health, and improving quality of life .

  Study Method-Random, double treatment of 6 months to 1 year with 87.5 mg / dose twice daily in 300 subjects aged 12-19 years who underwent Fontan surgery prior to age 5 Blind, placebo-controlled trial

The following are the criteria for inclusion in this study.
・ Men or women aged 12-19 years old ・ Fontan surgery before 5 years old

The following criteria are excluded from this study.
・ Height <132cm
• Hospitalization for acute decompensated heart failure within the last 12 months • Current intravenous inotropics • Evaluated for heart transplant or on list for transplant • Protein-leaking intestine Diagnosis of infectious disease, template bronchitis, cirrhosis-known Fontan intracardiac tunnel occlusion, pulmonary artery, resulting in a mean difference of> 4 mmHg between the proximal and distal regions of occlusion as measured by catheterization or echocardiography Branch stenosis or pulmonary vein stenosis • Physiology of one lung • Critical ventricular dysfunction qualitatively assessed by clinical echocardiography within 6 months before registration • Clinical echocardiography within 6 months before registration Serious valvular regurgitation, ventricular outflow stenosis, or aortic arch occlusion evaluated ・ Significant renal, liver, gastrointestinal, or bile duct disorders that can impair the absorption, metabolism, or excretion of orally administered drugs Cannot complete exercise testing at baseline screening • History of PDE5 inhibitor use within 3 months prior to study initiation • Use of other drugs to treat pulmonary hypertension within 3 months prior to study initiation Known intolerance to oral udenafil-Frequent use of drugs or other substances that inhibit or induce CYP3A4-Current use of alpa-blockers or nitrates-Prevent planned studies from completing successfully, Participating in or planning another study protocol that may invalidate the results. · Non-cardiac medical disorders that may prevent the planned study from completing successfully or invalidate the results. , Mental disorders, and / or social disorders ・ Treatment of heart disease that is ongoing or planned outside of the study center that may interfere with study completion ・ Women About: Being pregnant at the time of screening, planning to conceive before study completion, or refusing to use acceptable contraceptives during the study period • Grapefruit juice during the study period Cannot refrain from or restricting intake ・ Refusal to provide written informed consent / ascent ・ According to the opinion of a primary care physician, subjects are less compliant with the protocol Probability is high

  The trial will include a baseline measurement of the proposed pharmacodynamic (PD) endpoint and a quality of life study. For example, EndoPAT vascular assessment will be performed as the first PD test after obtaining an outlet. This must be done in the fasted state (from midnight until after the test) and without caffeine. After the blood vessel evaluation, the subject receives the target echocardiogram and evaluates ventricular function. A short break will be given after vascular assessment or after echocardiogram. Snacks will be provided. After vascular assessment, echocardiogram, and breaks, safety labs will be performed. This will include blood collection to assess serum creatinine and liver enzyme (aspartate aminotransferase and alanine aminotransferase) levels for all participants and a urine pregnancy test for female participants. If the pregnancy test is positive, all subsequent tests will be discontinued. The patient will not be enrolled in the trial. The results will be communicated to the subject and / or legal guardian by the institutional investigator according to the local IRB procedure. After safety testing, exercise testing will be successful using a brake-type bicycle ergometer according to the linear incremental load protocol previously published in the PHN Fontan cross-sectional study. After the exercise test, the subject will complete the baseline test. In addition, The Peds QL, cardiac specific Peds QL, and PCQLI will be enforced during the baseline study visit.

  The study coordinator will call each subject weekly for four weeks and then monthly to collect adverse events and answer questions related to the study.

  At the end of the study, subjects fast and visit in the absence of caffeine and first undergo a vascular function assessment, including undergoing a baseline study and a quality of life study again. Follow-up with subjects will be conducted 30 and 90 days after the end-of-study study and may be related to or possibly related to study drug that may occur within 90 days after completion of the protocol. Any additional adverse events related can be recorded.

Udenafil (87.5 mg twice a day) for a period of 6-12 months in adolescents with Fontan physiology is safe and well tolerated, even though there were no serious adverse events related to udenafil. Very little if any is expected. The severity of adverse events was determined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 MedDRA 12.1 (http://ctep.cancer.gov). Similarly, the effect of udenafil on pharmacodynamic outcomes, including exercise tolerance, echocardiographic measurements of ventricular function, endothelial function, and biomarkers associated with heart failure, is expected to improve during the course of treatment. Outcomes measured to determine the effectiveness of udenafil in this patient population will include:
• Exercise: Change in maximum oxygen uptake from baseline to end-of-study test as measured using standard exercise testing;
Echo: Change in myocardial performance index from baseline to end-of-trial study as measured by pulse Doppler echocardiography;
Endothelial function: change in logarithmically converted reactive hyperemia index obtained from the EndoPAT® device; and biomarker: change in serum BNP level from baseline to end of study.

In addition,
• Exercise: Measurement results below the maximum exercise tolerance will be collected and evaluated.
-Echo: Measurement results of systolic and dilated functions will be collected from the target echocardiogram.

  This study also included outcomes related to ventricular cavity size, flatness, and mass; mean dP / dt and peak systolic annulus velocity (S ′) during isotropic volumetric contraction (dP / dtic) of tissue Doppler Can be considered; systolic function estimated using diastolic; estimated based on diastolic function and MPI tissue Doppler; and qualitative and quantitative estimates of AV valve insufficiency.

  In addition, functional health is expected to improve after administration of udenafil. Changes in functional health status from baseline to end of study include full scale Peds QL, Peds QL physical function score, Peds QL psychosocial function score, Peds QL heart-specific module quality of life score, And / or can be measured using a pediatric heart quality of life inventory (PCQLI) score.

  In addition, genetic material is collected during the study to identify genetic determinants of response to udenafil after Fontan surgery in people with single ventricular lesions. This provides an indication of whether a particular subgroup of patients has a stronger positive response to udenafil compared to others. For example, the response to udenafil can be affected by variants involved in the vascular response to udenafil. Endothelial nitric oxide synthase gene variants have been reported to affect the response to sildenafil in patients with erectile dysfunction. This has not been studied for udenafil. The diversity of genes that regulate vascular inotropic and chronologic responses to exercise can affect the patient's exercise tolerance and response to udenafil after Fontan surgery. DNA will be preserved and genotyping studies will be conducted in the future to analyze genetic involvement in the response to udenafil.

  Additional covariate measures would include age, gender, race / ethnicity, height / weight, ventricular morphology, resting oxygen saturation, baseline pharmacodynamic test results, and current drug use, It is not limited to these. By observing these variables, it is possible to identify associations between various clinical factors and safety and PD outcomes.

  Data collection includes demographic information, including age, gender, race, ethnicity, heart structure, fontan surgery date, presence of fenestration, degree of atrioventricular regurgitation, grade of ventricular function, concomitant medications , And recording significant comorbidities. Safety data will be confirmed with each subject at each study visit and during a telephone visit. These events will be recorded and graded according to severity and relationship to study drug based on established criteria. Two additional telephone visits will take place 30 and 90 days after the end-of-study study to assess adverse events that may be related to or possibly related to study drug in the period following completion of the study procedure To do.

Other data collections include the following:
• Exercise test-Data from the brake cycle ergometer exercise measurement exercise test will be collected according to the protocol established by the PHN Fontan Crossing Study 3.
• Evaluation of ventricular function-Each test echocardiogram will be stored unspecified and sent to a core laboratory that performs data analysis and submits measurements to the PHN Data Coordination Center (DCC).
• Vascular Function Test-Unspecified data for the EndoPAT® test will be collected according to a standardized protocol. These data will be sent to the vascular core lab where they will analyze and submit measurements to the PHN DCC.
• Biomarkers-Serum for measurement of BNP levels will be sent to the core clinical lab. The result will be sent directly to the PHN DCC.
• Quality of Life Survey-The results of the Quality of Life Survey will be submitted to the PHN DCC.
• Biorepository samples-samples collected for biorepositories will be sent directly to the biorepository for future analysis.

  Subjects will be treated with other drugs at the physician's discretion. The current medication will be recorded on the test form at the study visit. Discontinuation of study drug is required if open-label use of any of the other PDE5 inhibitors is begun at any time during the study.

  When an individual subject completes the study, his / her cardiologist will be notified and the study medication will be discontinued. There is no need for the subject to stop taking the study drug. The determination of whether an individual subject will continue to use an uninsured PDE5 inhibitor will be determined by the subject and their cardiologist.

  While several preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications can be made to the embodiments without departing from the scope and spirit of the invention.

Claims (23)

  A method of treating, preventing, and / or minimizing a condition, symptom, and / or side effect associated with a patient undergoing Fontan surgery, wherein said patient has a therapeutically effective amount of udenafil or a pharmaceutically acceptable product thereof Administering a salt. The condition, symptom, and / or side effects are
(A) cardiac output, the method results in improved cardiac output;
(B) pulmonary vascular resistance, the method results in a decrease in pulmonary vascular resistance;
(C) exercise tolerance, the method results in an increase in exercise tolerance;
(D) myocardial performance, the method results in improved myocardial performance;
The method of claim 1, wherein (e) aerobic fitness, said method results in an improvement of aerobic fitness; or (f) any combination thereof. (A) cardiac output is about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and Improved by an amount selected from the group consisting of about 50%;
(B) pulmonary vascular resistance is about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about Reduced by an amount selected from the group consisting of 50%;
(C) Exercise tolerance is about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about Increased by an amount selected from the group consisting of 50%;
(D) Myocardial performance is about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about 50 Improved by an amount selected from the group consisting of:
(E) aerobic exercise capacity of about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%; and 3. The method of claim 2, wherein the method is improved by an amount selected from the group consisting of about 50%; or (f) any combination thereof.   The method according to any one of claims 1 to 3, wherein the patient who has undergone the Fontan operation is a human patient. The patient is (a) an adult human patient older than 18 years;
(B) a pediatric patient of about 2 to about 18 years of age;
5. The method of claim 4, wherein (c) is a pediatric patient about 12 to about 18 years old; or (d) is a pediatric patient about 12 to about 16 years old.   The method of claim 1, wherein the udenafil or the pharmaceutically acceptable salt thereof is a solid oral dosage form.   The method according to claim 6, wherein the solid oral dosage form is a tablet or a capsule.   The method of claim 1, wherein the udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 25 mg to about 600 mg.   9. The method of claim 8, wherein the udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 37.5 mg, about 75 mg, about 87.5 mg, about 125, or about 175 mg.   2. The method of claim 1, wherein the udenafil or a pharmaceutically acceptable salt thereof is administered once a day.   11. The method of claim 10, wherein a once-daily therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof provides a therapeutic level of udenafil that is present in the patient's bloodstream for up to about 8 hours. .   A therapeutic level of udenafil is present in the patient's bloodstream up to about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 12. The method of claim 11, wherein there is a time selected from the group consisting of 21, about 22, about 23, and about 24 hours.   The method of claim 1, wherein the udenafil or a pharmaceutically acceptable salt thereof is administered twice a day.   The twice-daily administration of a therapeutically effective dose of udenafil or a pharmaceutically acceptable salt thereof results in a therapeutic level of udenafil present in the patient's bloodstream for at least about 16 hours of the 24-hour administration period. Item 14. The method according to Item 13.   The therapeutic level of udenafil is in the patient's bloodstream at least about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 15 hours, about 24 hours. 15. The method of claim 14, wherein the method is present for a period of 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. 2. The method of claim 1, wherein (a) the patient does not experience any serious adverse event; or (b) the patient does not experience any moderate adverse event. (A) VO2 at maximum effort is maintained over time;
(B) VO2 at maximum effort over time is less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, or less than about 40% Decreased;
(C) Maximum effort VO2 is improved by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%;
(D) VO2 at the anaerobic metabolic threshold is maintained over time;
(E) VO2 at an anaerobic metabolic threshold over time is less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, or Or less than about 40%; or (f) VO2 at the anaerobic threshold is at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about The method of claim 1, wherein the method improves by 45%, or about 50%. (A) exercise tolerance is maintained over a long period of time;
(B) Reduced exercise tolerance over time by less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, or less than about 40% Or (c) Exercise tolerance is improved by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. The method of claim 1. (A) vascular function is maintained over time;
(B) Reduced vascular function over time by less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, or less than about 40%. ;
(C) vascular function is improved by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%; and / or (D) Vascular function is any of PAT index, pulse amplitude tonometry, natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the concentration curve relative to maximum occlusion / control, and average to maximum occlusion / control The method of claim 1, which is measured by: (A) ventricular function is maintained over time;
(B) Decreased ventricular function over time by less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, or less than about 40%. ;
(C) ventricular function is improved by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%; and / or The method of claim 1, wherein (d) ventricular function is measured by any one of myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, and mean isovolumetric contraction and relaxation.   The method of claim 1, wherein the blood pool MPI is improved by at least 20%.   2. The method of claim 1, wherein administering a therapeutically effective amount of udenafil or a pharmaceutically acceptable salt thereof results in a characteristic pharmacokinetic profile. The characteristic pharmacokinetic profile is
(A) 300-700 ng / ml C _max ;
(B) a C _{max of} about 500 ng / ml;
(C) T _{max for 1 to} 1.6 hours;
(D) T _{max of} about 1.3 hours;
(E) 2UC-4150 ng · hr / ml AUCτ;
(F) AUCτ of about 3350 ng · hr / ml;
(G) 5110-8290 ng · h / ml AUC _0-24 ;
(H) AUC _0-24 which is about 6701 ng · hr / ml.
23. The method of claim 22 comprising: